Ultrasonic transducers and imaging systems are used in many medical applications and, in particular, for the non-invasive acquisition of images of organs and conditions within a patient, typical examples being the ultrasound imaging of fetuses and the heart. Such systems commonly use a linear or phased array transducer having multiple transmitting and receiving elements to transmit and receive narrowly focused and "steerable" beams, or "lines", of ultrasonic energy into and from the body. The received beams, or lines, are reflected from the body's internal structures and contain amplitude or phase information, or both, that is used to generate images of the body's internal structures.
A primary problem in ultrasonic imaging has been that many of the body's internal structures have similar characteristics as regards the reflection of ultrasonic energy, so that it is difficult to obtain as clear and detailed images of many of the structures as is desired. In particular, many of the structures of interest, such as the muscles of the heart, are perfused with blood, so that it is difficult to distinguish between blood vessels and the chambers of the heart and the heart muscles.
This problem led to the development of alternative methods for imaging certain of the body's structures, such as the blood vessels of the heart. One of the most common imaging techniques, for example, is referred to as an angiogram and requires the injection of a radiofluorescent dye into the vessels to image the blood vessels of the heart with x-rays. Such techniques, however, are invasive or are otherwise unsatisfactory. For example, the use of x-ray imaging carries the risk of potential injury from radiation and involves complex, expensive and hazardous equipment. Also, radiofluorescent dyes are potentially toxic to at least some patients and are not broken down in the body but are flushed from the body by natural waste processes, often requiring hours to disappear from the body.
A more recent development has been ultrasonic imaging using contrast agents injected into the blood stream. Ultrasonic contrast agents are now commercially available and are essentially small bubbles of gas, such as air, formed by agitating a liquid or bubbling gas through a liquid, such as a saline solution or a solution containing a bubble forming compound, such as albumin. When insonicated, the bubbles resonate at their resonant frequency and emit energy at both the fundamental and second harmonic of their resonant frequency, thereby returning an enhanced signal at or around these frequencies and thereby providing an enhanced image of the liquid or tissue containing the contrast agent. It is also well known that the bubbles "disappear" when insonicated and the current theory is that the insonication ruptures the bubble's shell, thereby allowing the gas to dissipate into the surrounding liquid or tissue.
The use of ultrasonic contrast agents is thereby advantageous in allowing enhanced imaging using ultrasonics rather than x-rays, thereby eliminating the radiation hazard and allowing the use of equipment that is significantly less expensive and hazardous to use. Also, the agents are non-toxic and dissolve relatively quickly into waste products, such as air and albumin, that are normally found in the body and that are themselves non-toxic. Further, the insonication of the agent in itself destroys the agent, so that the agent can effectively be "erased" during the imaging process to a degree.
There are, however, a number of persistent problems in ultrasonic imaging using contrast agents. For example, it is important to be able to measure the rate of blood flow through tissues such as the heart muscles in order to detect damaged tissues or tissues having insufficient blood flow, such as may occur when an artery is partially or completely blocked. While there have been attempts to measure the perfusion of blood containing a contrast agent in tissues such as the heart muscles to thereby measure the volume of blood in the heart tissues, the results have been unsatisfactory because blood volume is not directly dependent on rate of blood flow.
Yet another problem is control of the concentration of contrast agent in a region of interest. That is, it is well known that the concentration of contrast agent in a region of interest is critical to the images obtained therefrom because the intensity of the image, that is, the amplitude of the returned scanning signal, will increase with an increase in concentration of the contrast agent up to a certain point, and will then plateau. As a consequence, too low a concentration will result in poorly enhanced images. Too high a concentration, however, will result in agent saturation and "washing out" of at least portions of the image as the concentration of agent in the corresponding volumes of tissue reach the plateau concentration, so that various volumes of the tissue cannot be distinguished by differences in concentrations of the agent.
While there are various reasons for this effect, one is that the saturation of agent particles in a given region results in a non-linear increase in intensity in the image due to interference between the particles that reduces the total reflection. This effect appears to become significant when the concentration is such that the particles or bubbles are, on the average, within one transmit frequency wavelength of each other.
Another related problem is a shadowing effect wherein the ultrasonic energy is absorbed or reflected by the agent in a bolus or body of the agent in the near field of the scan line, that is, when a volume of agent that is nearer to the transducer than the region of interest generates a return that overshadows the return from the region of interest. Since the ultrasonic energy that reaches the region of interest is thereby attenuated more than what would normally be returned from the effects of the tissue in the region of interest, the return signal is of a lower intensity than normal and the density of contrast agent in the region of interest is therefore underestimated. Accordingly, and for example, a spatial average measure of intensity in a region of interest that included a shadowed region would underestimate the concentration of contrast agent therein, resulting in degradation of the resulting image. Too high a concentration of contrast agent in the regions between the transducer and the region of interest will thereby result in a shadowing effect wherein the near region image return will shadow, that is, hide or at least degrade the image in the region of interest.
Yet another related problem arising from an inability to control the concentration of contrast agent in a region of interest is a result of the depletion of the contrast agent as a side effect of the normal imaging process if the concentration of agent is too high. That is, if the contrast agent is too concentrated, it tends to absorb the acoustic energy of the scan beam in the near field of the acoustic transducer, thereby not only shadowing the agent in the far-field of the transducer beam as described above but also resulting in disproportionate depletion of the agent in the near field relative to the depletion of the agent in the far-field. This differential depletion, in turn, interferes with the detection and measurement of the agent in the far field.
Still other problems are related to the detection and measurement of the actual concentration of contrast agent in tissues of liquids, rather than the mere presence of a contrast agent, because it is difficult to detect boundaries between liquids and tissues, particularly as the agents permeate both the liquid transporting the agent, such as blood, and the tissues because the agents are transported into the tissues with the blood.
Another and related problem associated with the use of ultrasonic contrast agents arises from the practice that, like radiofluorescent dyes, the agents are preferably introduced into the body through a vein, where the blood is at a relatively low pressure, rather than an artery, where the blood is at a relatively high pressure. As a consequence, the agent must flow through a considerable path through the body, such as the lungs and the heart, before reaching the regions of interest, such as the arteries and chambers of the heart. The contrast agent therefore does not reach the region of interest as a sharply defined "bolus" or body of agent enhanced blood, but as a diffuse "cloud" that increases and decreases in concentration gradually.
The object of the process, however, is to differentiate between healthy tissue, which perfuses rapidly, and stunned, hibernating or infarcted tissue, which perfuses slowly, if at all. When the bolus appears at the tissues of interest as a diffuse cloud, the enhancing agent will often perfuse into the tissue at a rate that is determined by the gradient of the edge of the cloud rather than by the perfusion rate of the tissues, and a rate that is often less than the perfusion rate of healthy tissue. As a result, the delineation between healthy and infarcted tissues is blurred and the resulting image is of low resolution.
The prior art has attempted to solve this problem for radiofluorescent dyes by using a catheter introduced into an artery as far as possible from the heart, such as at the upper leg, and passed through the arteries to the region of the heart to transport the dye to a point near or in the heart before introducing the dye into the bloodstream. This procedure, however, is invasive and risks damage to the arteries or heart and it is often difficult to prevent or stop subsequent bleeding from the artery at the point the catheter was inserted.
The present invention provides a solution to these and other problems of the prior art by providing improved methods for the use of contrast agents.